Because leukotrienes have been implicated as important mediators of asthma, allergy, arthritis, psoriasis, and inflammation, agents that inhibit biosynthesis of leukotrienes offer treatment for leukotriene mediated afflictions in man and animals. N-benzo[b]thienyl-N-hydroxyureas, as exemplified by N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyurea (zileuton, U.S. Pat. No. 4,873,259) are potent leukotriene biosynthesis inhibitors. However, N-benzo[b]thienyl-N-hydroxyureas have proven to be a synthetic challenge commercially.
The synthesis of zileuton offers several illustrations of typical methods to prepare benzo[b]thienyl substituted N-hydroxyureas. In one case, one begins by reacting 2-acetylbenzo[b]thiophene with hydroxylamine to form the corresponding oxime. Then the oxime is reduced with an excess of reducing agent, generally borane-pyridine complex, to form 1-benzo[b]thien-2-ylethyl hydroxylamine. Finally, the hydroxylamine is reacted with trimethylsilyl isocyanate or sodium or potassium cyanate to form the corresponding N-hydroxyurea by (see U.S. Pat. No. 4,873,259). Due to the safety considerations and cost involved in using excess reducing agent on a large scale, several alternative preparations of N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyureas have been devised.
One alternative involves reacting (1-benzo[b]thien-2-yl)-1-chloroethane with a nitrogen nucleophile. The nitrogen moiety is then converted to the N-hydroxyurea. However, direct displacement of chloride with hydroxylamine gives a mixture of N- and O-alkylation. Therefore, an O-protected hydroxylamine derivative such as O-benzylhydroxylamine is used as the nitrogen nucleophile (see U.S. Pat. No. 4,873,259). Then the product of the displacement reaction is deprotected to give 1-benzo[b]thien-2-ylethyl hydroxylamine. The hydroxylamine is then converted to the N-hydroxyurea as described above. The displacement has also been accomplished using Z-furfuraldehyde oxime and base to give the nitrone, which is hydrolyzed with acid or reacted with hydroxylamine to give 1-benzo[b]thien-2-ylethyl hydroxylamine (see U.S. Pat. No. 4,873,259). Other O-protected nitrogen nucleophiles such as O-protected hydroxyurea derivatives, for example O-(tetrahydropyran-2-yl)-N-hydroxyurea, have also been used to displace chloride. Removal of the oxygen protecting group provides the N-hydroxyurea (see U.S. Pat. No. 5,292,900).
One process circumvents the conversion of the (1-benzo[b]thien-2-yl)-1-hydroxyethane to the corresponding chloride by using the Mitsunobu coupling. In this process, one first reacts (1-benzo[b]thien-2-yl)-1-hydroxyethane with N,O-bis(phenoxycarbonyl)hydroxylamine. Then, one obtains the corresponding N-hydroxyurea by aminolysis (see A. O. Stewart and D. W. Brooks, J. Org. Chem., 57 (18), 5020 (1992).
The processes described above require either many synthetic steps, and/or protection and deprotection of the hydroxylamine which is expensive and inefficient on a large scale. The pharmaceutical manufacturing industry still seeks a N-substituted-N-hydroxyurea synthesis that can be accomplished in a few steps with a minimum amount of expensive reducing agents or protecting groups.